Process for the preparation of the (-)-antipode of (E)-1-cyclohexyl-4, 4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene

ABSTRACT

A process for the preparation of the (-)-antipode of (E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene of the formula ##STR1## which comprises reacting the (E)-isomer of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of the formula ##STR2## (a) with boron hydride in the presence of an optically active proline derivative of the formula ##STR3## in which, R 1  is alkyl, phenyl or benzyl, or 
     (b) with a complex borohydride in the presence of an acid addition salt of the optically active proline derivative, in the presence of a diluent at a temperature between about -70° C. and +60° C. The proline derivatives are also new and are produced from S-proline esters. The end product is a known plant growth regulant.

The present invention relates to a new process for the preparation ofthe known (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-ene.

The (-)-antipode here is in each case to be understood as thatenantioner which rotates the plane of oscillation of linearly polarizedlight of the sodium D line to the left.

It has already been disclosed that the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-enecan be prepared by reacting the corresponding racemic compound with anoptically active acid chloride, resolving the resulting esterdiastereomer mixture chromatographically and hydrolyzing the ester whichcontains the (-)-antipode. See U.S. Pat. No. 4,592,772 issued June 3,1986. The disadvantage of this process, however, is that it is onlysuitable for the synthesis of small amounts of the desired antipode.

It has furthermore already been disclosed that ketones can be reducedwith reducing agents in the presence of various chiral auxiliaryreagents to give optically active carbinols (compare Chem. Pharm. Bull.31 837 (1983) and EP-OS (European Published Specification) No.0,054,431). It is unsatisfactory, however, that this process is notgenerally applicable. Thus, ketones which contain no aromatic groups canonly be converted into carbinols which have an optical purity which isinadequate for practical purposes.

It is moreover known that the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-enecan be synthesized by reducing the (E)-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one withboron hydrides in the presence of (-)-norephedrine (compare EP-OS(European Published Specification) No. 142,566). A decisive disadvantageof this process, however, is that the optical purity of the desiredproduct is relatively low.

It has now been found that the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneof the formula ##STR4## is obtained by a process in which the (E)-isomerof 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one ofthe formula ##STR5## is reacted (a) with boron hydride in the presenceof an optically active proline derivative of the formula ##STR6## inwhich R¹ represents alkyl, phenyl or benzyl, or

(b) with complex borohydrides in the presence of an acid addition saltof an optically active proline derivative of the formula (III) in thepresence of a diluent at temperatures between -70° C. and +60° C.

It is to be described as exceptionally surprising that the (-)-antipodeof(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneof the formula (I) can be prepared in a very high yield and excellentoptical purity by the process according to the invention, since on thebasis of the known prior art it could not be expected that the reactionleads selectively to the desired product. Above all, it was not to beexpected that the reaction also proceeds virtually free from sidereactions at relatively high temperatures.

The process according to the invention is distinguished by a number ofadvantages. Thus, the reaction components are also available inrelatively large amounts and can also be handled without problems on anindustrial scale. The expenditure on apparatus necessary to carry outthe process is furthermore low, and working up of the reaction mixtureobtained when the reaction has ended presents no difficulties. Inparticular, however, the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneof the formula (I) can be prepared in a higher yield and a betteroptical purity by the process according to the invention than by themethods previously known.

The (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-enewhich can be prepared by the process according to the invention isunambiguously characterized by formula (I). In this formula, theasymmetrically substituted carbon atom, which represents the chiralitycenter, is labelled by an (*). The letter "E" before the systematic nameof the compound of the formula (I) expresses that the cyclohexyl radicaland the 1,2,4-triazolyl radical are on opposite sides of the doublebond.

If boron hydride is used as the reducing agent,S-2-(dibenzyl-hydroxymethyl)-pyrrolidine is used as the chiral auxiliaryreagent and tetrahydrofuran (=THF) is used as the diluent, the course ofthe process according to the invention (variant a) can be represented bythe following equation: ##STR7##

If sodium boranate is used as the reducing agent and the hydrochlorideof S-2-(dibenzyl-hydroxymethyl)pyrrolidine is used as the chiralauxiliary reagent, the course of the process according to the invention(variant b) can be principle likewise be illustrated by the equationshown above.

The E-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of theformula (II) required as a starting material in carrying out the processaccording to the invention is already known (compare DE-OS (GermanPublished Specification) No. 3,322,181).

In carrying out the process according to the invention, either boronhydride (variant a) or complex borohydrides (variant b) function as thereducing agent. Sodium boranate is a preferred possible complexborohydride here.

Formula (III) provides a general definition of the optically activeproline derivatives (=substituted hydroxymethyl-pyrrolidines) requiredas chiral auxiliary reagents in carrying out the process according tothe invention (variant a). In this formula, R¹ preferably representsalkyl with 1 to 6 carbon atoms, phenyl or benzyl.

Possible acid addition salts of optically active proline derivatives incarrying out variant (b) of the process according to the invention are,preferably, those compounds which are formed by addition of hydrogenhalide acids, such as, for example, hydrochloric or hydrobromic acid, orfurthermore sulphuric acid, nitric acid, phosphoric acid ornaphthalene-1,5-disulphonic acid, onto optically active compounds of theformula (III).

In the proline derivatives of the formula (III) or acid addition saltsthereof which are used as chiral auxiliary reagents in carrying out theprocess according to the invention, the asymmetrically substitutedcarbon atom has the S-configuration.

The optically active proline derivatives of the formula (III) and acidaddition salts thereof were not previously known. They can be preparedby a process in which either

(c) S-proline esters of the formula ##STR8## in which R² representsalkyl with 1 to 4 carbon atoms,

are reacted with Grignard compounds of the formula

    R.sup.1 --MgX                                              (V)

in which

R¹ has the abovementioned meaning and

X represents chlorine, bromine or iodine,

in the presence of a diluent, or

(d) S-proline esters of the formula ##STR9## in which R² has theabovementioned meaning,

are reacted in a first stage with benzyl chloroformate of the formula##STR10## in the presence of an acid-binding agent and in the presenceof a diluent, and the resulting esters with the S-configuration on theasymmetrically substituted carbon atom, of the formula ##STR11## inwhich R² has the abovementioned meaning,

are then reacted in a second stage with Grignard compounds of theformula

    R.sup.1 --MgX                                              (V)

in which

R¹ and X have the abovementioned meaning,

in the presence of a diluent, and finally the S-proline derivativesthereby obtained, of the formula ##STR12## in which R¹ has theabovementioned meaning,

are reacted in a third stage with hydrogen in the presence of a catalystand in the presence of a diluent, and, if appropriate, an acid is alsoadded.

Formula (IV) provides a definition of the S-proline esters required asstarting substances in the preparation of the optically active prolinederivatives of the formula (III). In this formula, R² preferablyrepresents methyl or ethyl. In each case those compounds which have theS-configuration on the asymmetrically substituted carbon atoms are used.

The S-proline esters of the formula (IV) are known or can be prepared ina simple manner by processes which are known in principle.

Formula (V) provides a general definition of the Grignard compoundsrequired as reaction components in processes (c) and (d). In thisformula, R¹ preferably has those meanings which have already beenmentioned as preferred for this radical in connection with thedescription of the compounds of the formula (III). X representschlorine, bromine or iodine.

The Grignard compounds of the formula (V) are generally known compoundsof organic chemistry. Benzyl chloroformate of the formula (VI) and itsuse as a protective group are likewise known.

Possible diluents in carrying out process (c) are all the customaryinert organic solvents. Solvents which can preferably be used areethers, such as diethyl ether, tetrahydrofuran and dioxane.

The reaction temperatures can be varied within a certain range incarrying out process (c). The reaction is in general carried out attemperatures between -10° C. and +80° C., preferably between 0° C. and+60° C.

In carrying out process (c), 5 to 10 mols of Grignard compound of theformula (V) are employed per mol of S-proline ester of the formula (IV).Working up is carried out by customary methods. In general, a procedureis followed in which the reaction mixture is hydrolyzed with water,aqueous ammonium chloride solution is then added and the organic phaseis separated off, washed, dried and, after being concentrated,distilled.

Possible acid-binding agents in carrying out the first stage of process(d) are all the customary acid acceptors. Acid acceptors which canpreferably be used are tertiary amines, such as triethylamine,N,N-dimethylaniline, pyridine, N,N-dimethylaminopyridine,diazabicyclooctane (DABCO), diazabicyclononene (DBN) ordiazabicycloundecene (DBU).

Possible diluents in carrying out the first stage of process (d) are allthe customary inert organic solvents. Solvents which can preferably beused are ethers, such as diethyl ether, tetrahydrofuran or dioxane.

The reaction temperatures can be varied within a certain range incarrying out the first stage of process (d). The reaction is in generalcarried out at temperatures between -10° C. and +60° C., preferablybetween 0° C. and +50° C.

In carrying out the first stage of process (d), in general 1 to 1.5 molsof benzyl chloroformate of the formula (IV) and 1 to 1.5 mols ofacid-binding agent are employed per mol of S-proline ester of theformula (IV). Working up is carried out by customary methods. Ingeneral, a procedure is followed in which water is added to the reactionmixture, the mixture is then extracted with an organic solvent of lowwater-solubility and the combined organic phases are washed and, afterbeing concentrated, distilled.

Possible diluents in carrying out the second stage of process (d) areall the customary inert organic solvents. Solvents which can preferablybe used are ethers, such as diethyl ether, tetrahydrofuran and dioxane.

The reaction temperatures can likewise be varied within a certain rangein carrying out the second stage of process (d). The reaction is ingeneral carried out at temperatures between -10° C. and +80° C.,preferably between 0° C. and +60° C.

In carrying out the second stage of process (d), in general 2 to 5 molsof Grignard compound of the formula (V) are employed per mol of acompound of the formula (VII). Working up is carried out by customarymethods. In general, a procedure is followed in which the reactionmixture is hydrolyzed with water and then acidified and extracted withan organic solvent of low water-miscibility and the combined organicphases are washed and, after being dried, concentrated.

Possible catalysts in carrying out the third stage of process (d) areall the reaction accelerators customary for such reactions. Reactionaccelerators which can preferably be used are palladium or platinum oncharcoal.

Possible diluents in carrying out the third stage of process (d) are allthe customary inert organic solvents. Solvents which can preferably beused are alcohols, such as methanol and ethanol, and furthermore ethers,such as diethyl ether, tetrahydrofuran and dioxane.

The reaction temperatures can also be varied within a certain range incarrying out the third stage of process (d). The reaction is in generalcarried out at temperatures between 0° and 40° C., preferably between10° and 30° C.

In carrying out the third stage of process (d), the hydrogenation iscarried out with an excess of hydrogen under a pressure of 1 to 10 bar.Working up is carried out by customary methods. In general, a procedureis followed in which the catalyst is filtered off, an organic solvent oflow water-solubility is added to the reaction mixture which remains, ifappropriate after prior acidification, and the desired product is thenisolated by filtration or concentration.

Acids which are possible for the preparation of acid addition salts ofthe compounds of the formula (III) are, preferably, those which havealready been mentioned as acids which are preferably to be added inconnection with the description of these salts.

The acid addition salts of the compounds of the formula (III) can beobtained in a simple manner by customary salt formation methods, suchas, for example, by dissolving a compound of the formula (III) in asuitable inert solvent and adding the acid, such as, for example,hydrochloric acid, and they can be isolated in a known manner, forexample by filtration, and if appropriate purified by washing with aninert organic solvent. In the process (d) described above, acid additionsalts of compounds of the formula (III) are preferably prepared by aprocedure in which the acid in question and an inert organic solvent areadded to the mixture obtained after hydrogenation, after removal of thecatalyst, and the salt which separates out as crystals is filtered off.

Possible diluents in the process according to the invention for thepreparation of the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneof the formula (I) are all the customary organic solvents for suchreactions. Solvents which are preferably possible are halogenatedhydrocarbons, such as methylene chloride, and furthermore ethers, suchas diethyl ether, tert.-butyl methyl ether, tetrahydrofuran, dioxane andanisole.

The reaction temperatures can be varied within a certain range incarrying out the process according to the invention. The reaction is ingeneral carried out at temperatures between -70° C. and +60° C.,preferably between -30° C. and +50° C.

The process according to the invention is in general carried out undernormal pressure.

In carrying out the process according to the invention, in general 1 to4 mols, preferably 1.3 to 3 mols, of boron hydride or complexborohydride and 1 to 3 mols, preferably 1.2 to 2 mols, of opticallyactive proline derivative of the formula (III) or an acid addition saltof an optically active proline derivative of the formula (III) areemployed per mol of (E)-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of theformula (II).

In carrying out the process according to the invention, a procedure isin general followed in which the reducing agent is added at temperaturesof between -30° C. and +30° C. to a solution of the optically activeproline derivative or acid addition salt of the optically active prolinederivative in an organic solvent, the (E)-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of theformula (II) is then added at temperatures between 20° and 50° C. andthe mixture is stirred at temperatures between 20° and 50° C. forseveral hours. Working up is carried out by customary methods. Ingeneral, a procedure is followed in which water or an acid and water areadded to the reaction mixture, the mixture is then extracted with anorganic solvent of low water-solubility and the combined organic phasesare concentrated, if appropriate after prior washing. The residue whichremains can be further purified by digestion with suitable organicsolvents or by recrystallization or chromatographically.

The (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneof the formula (I) which can be prepared by the process according to theinvention and its use for regulating plant growth are known. See U.S.Pat. No. 4,592,772, issued June 3, 1986.

The process according to the invention is illustrated by the followingexamples.

Preparation Examples EXAMPLE 1 ##STR13##

29 ml (0.029 mol) of boron hydride-tetrahydrofuran complex are added toa solution of 4.1 g (0.0145 mol) ofS-2-(dibenzyl-hydroxymethyl)-pyrrolidine in 30 ml of absolutetetrahydrofuran at 20° C., with stirring. After the mixture has beenstirred at 20° C. for 30 minutes, 2.61 g (0.01 mol) of the (E)-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one areadded and the mixture is stirred at 40° C. for a further 16 hours.Thereafter, the reaction mixture is poured into 100 ml of 2N aqueoushydrochloric acid. The mixture formed is extracted twice with methylenechloride and the combined organic phases are concentrated under reducedpressure. The residue which remains is chromatographed with a mixture ofchloroform/ethyl acetate=4:1 on silica gel. 2.3 g (87% of theory) of the(-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneare obtained in this manner in the form of a crystalline product.

Melting point: 150° C.

[α]_(D) ²⁰ =-61.4° (c=0.520/CHCl₃)

The product has an optical purity of 83% e.e.

EXAMPLE 2 ##STR14##

0.68 g (0.018 mol) of sodium boranate is added to a suspension of 5.2 g(0.018 mol) of S-2-(dibenzyl-hydroxymethyl)-pyrrolidine hydrochloride in75 ml of absolute tetrahydrofuran at -30° C., with stirring. Thetemperature is allowed to rise gradually to 20° C. and stirring iscontinued at 20° C. for a further 2 hours. Thereafter, 3.15 g (0.012mol) of the (E)-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one areadded dropwise and the mixture is stirred at 40° C. for 20 hours. Thereaction mixture is then poured into water. The resulting mixture isextracted with ethyl acetate and the combined organic phases areconcentrated uner reduced pressure. The residue which remains ischromatographed with a mixture of chloroform/ethyl acetate=4:1 on silicagel. 2.1 g (67% of theory) of the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneare obtained on this manner in the form of a crystalline product.

Melting point: 148°-150° C.

[α]_(D) ²⁰ : -62.3° (c=0.464/CHCl₃).

The product has an optical purity of 79.3% e.e. (according tochromatographic determination).

EXAMPLE 3 ##STR15##

13 g (0.1 mol) of S-proline methyl ester are added dropwise, whilestirring and cooling with ice, to a Grignard compound prepared from 25 g(1 mol) of magnesium and 127 g (1 mol) of benzyl chloride in 350 ml ofether. The reaction mixture is warmed and is boiled under reflux for 2hours. Thereafter, hydrolysis is carried out by slow addition of water.The reaction mixture thus formed is poured into 1.5 liters of saturatedaqueous ammonium chloride solution. The organic phase is separated offand the aqueous phase is extracted once again with ether. The combinedorganic phases are washed with dilute aqueous sodium hydroxide solutionand then dried and concentrated under reduced pressure. The residuewhich remains is distilled under a high vacuum. 19.7 g (70% of theory)of S-2-(dibenzyl-hydroxymethyl)-pyrrolidine are obtained in this mannerin the form of a liquid.

Boiling point: 165°-170° C./0.03 mbar.

[α]_(D) ²⁰ =+9.6° (c=0.581/CH₃ OH).

EXAMPLE 4 ##STR16##

13 g (0.1 mol) of S-proline methyl ester are added dropwise, whilestirring and cooling with ice, to a Grignard compound prepared from 25 g(1 mol) of magnesium and 157 g (1 mol) of bromobenzene in 350 ml ofether. The reaction mixture is warmed, and is boiled under reflux for 2hours. Thereafter, hydrolysis is carried out by slow addition of water.The reaction mixture thus formed is poured into 1.5 liters of saturatedaqueous ammonium chloride solution. The combined organic phases arewashed with dilute aqueous sodium hydroxide solution and then dried andconcentrated under reduced pressure. The residue which remains ischromatographed with ethyl acetate on silica gel. 10.8 g (22% of theory)of S-2-(diphenylhydroxymethyl)-pyrrolidine are obtained in this mannerin the form of a viscious product.

EXAMPLE 5 ##STR17##

1st stage: ##STR18##

180 g (1.01 mol) of benzyl chloroformate are added dropwise to asolution of 130 g (1 mol) of S-proline methyl ester and 155 ml (1.1 mol)of triethylamine in 600 ml of absolute tetrahydrofuran at a temperaturebetween 0° C. and 10° C., while stirring, a colorless precipitateseparating out. The reaction mixture is left to stand at roomtemperature for 16 hours and is then poured into 1.5 liters of water.The resulting mixture is extracted several times with ethyl acetate. Thecombined organic phases are washed first with dilute aqueoushydrochloric acid and then with water and are concentrated under reducedpressure. The residue which remains is distilled under a high vacuum.188 g (72% of theory) of N-benzyloxycarbonyl-S-proline methyl ester ofboiling point 160° C./0.1 mbar are obtained in this manner.

2nd stage: ##STR19##

A solution of 87 g (0.33 mol) of N-benzyloxycarbonyl-S-proline methylester in 200 ml of absolute ether is added dropwise, while stirring andat 0° C., to a Grignard compound prepared from 28 g (1 mol) of magnesiumand 171 g (1 mol) of benzyl bromide in 400 ml of absolute ether. Thereaction mixture is left to stand at room temperature for 16 hours andis then hydrolyzed by addition of water. It is then acidified withconcentrated hydrochloric acid and extracted with ethyl acetate. Thecombined organic phases are washed with water, dried and concentratedunder reduced pressure. 163 g of a yellow oil which, according to thegas chromatogram, consists ofN-benzyloxycarbonyl-S-2-(dibenzyl-hydroxymethyl)-pyrrolidine to theextent of 50%, are obtained in this manner. The yield is accordinglycalculated as 59.9% of theory.

3rd stage: ##STR20##

A solution of 75 g of the crude product containing 50% ofN-benzyloxycarbonyl-S-2-(dibenzyl-hydroxymethyl)-pyrrolidine in 300 mlof ethanol is hydrogenated with 10 g of palladium-on-charcoal (5%strength) with hydrogen under a pressure of 5 bar at 20° C. for 5 hours.After the catalyst has been filtered off with suction, a vigorous streamof hydrogen chloride is passed into the solution, while cooling. Thereaction mixture is then concentrated by stripping off the solvent underreduced pressure and 300 ml of ethyl acetate are added to the oilyproduct which remains. The precipitate which thereby crystallizes out isfiltered out with suction. 25 g (87.5% of theory, based on a 50% purestarting substance) of S-2-(dibenzyl-hydroxymethyl)-pyrrolidinehydrochloride are obtained in this manner.

Melting point: 130° C.

Treatment of the salt thus prepared with dilute aqueous sodium hydroxidesolution gives free S-2-(dibenzyl-hydroxymethyl)-pyrrolidine, which isidentical to the product described in Example 3.

It is understood that the specification and examples are illustrativebut not limitative of the present invention and that other embodimentswithin the spirit and scope of the invention will suggest themselves tothose skilled in the art.

I claim:
 1. A process for the preparation of the (-)-antipode of(E)-1-cyclohexyl-4,4-dimethyl-3-hydroxy-2-(1,2,4-triazol-1-yl)-pent-1-eneof the formula ##STR21## which comprises reacting the (E)-isomer of1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one of theformula ##STR22## (a) with boron hydride in the presence of an opticallyactive proline derivative of the formula ##STR23## in which R¹ is phenylor benzyl, or(b) with a complex borohydride in the presence of an acidaddition salt of the optically active proline derivative, in thepresence of a diluent at a temperature between about -70° C. and +60° C.2. A process according to claim 1, wherein the optically active prolinederivative is S-2-(dibenzyl-hydroxymethyl)-pyrrolidine.
 3. A processaccording to claim 1, wherein the optically active proline derivativeacid addition salt is S-2-(dibenzyl-hydroxymethyl)-pyrrolidinehydrochloride.
 4. A process according to claim 1, wherein the complexborohyride is sodium boranate.
 5. A process according to claim 1,wherein the temperature is between about -30° C. and +50° C.